GENETIC APPROACHES TO SEROTONIN AND FEEDING BEHAVIOR

血清素和喂养行为的遗传学方法

• 批准号: 6758545
• 负责人: Laurence H. Tecott
• 金额: $ 33.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758545
• 关键词: appetite; behavioral /social science research tag; behavioral genetics; bioenergetics; body physical activity; brain mapping; eating disorders; genetic models; genetic susceptibility; laboratory mouse; mutant; neuroregulation; nutrient intake activity; nutrition related tag; obesity; serotonin receptor

DESCRIPTION: (Adapted from the Investigator's Abstract) Brain serotonin systems are strongly implicated in the regulation of normal feeding behavior and in the dysregulation of feeding observed in eating disorders. Several lines of evidence indicate that serotonin 5-HT2C receptor subtype contributes significantly to the serotonergic inhibition of food intake. Consistent with this, mice lacking functional setotonin 5-HT2C receptors display reduced sensitivity to appetite suppressant drugs that act through serotonin systems. In addition, these animals exhibit a dysregulation of feeding behavior leading to chronic elevations of food intake, late-onset ('middle-age") obesity and enhanced susceptibility to type 2 diabetes. Several features of this obesity syndrome are reminiscent of common forms of the human condition. It is proposed that 5-HT2C receptor mutants provide a unique genetic model in which obesity results from a primary defect in feeding behavior rather than a direct effect of the mutation on energy expenditure. In addition to testing this hypothesis, the neural mechanisms through which 5-HT2C receptors regulate feeding will be explored. In Aim 1, detailed studies of feeding behavior will be performed to test the hypothesis that 5-HT2C receptor mutants compensate for their overeating by increasing energy expenditure and that subsequent obesity results from an age dependent failure to maintain this compensation. In aim 3, mechanisms through which serotonin systems compensate for the 5-HT2C receptor mutation will be explored. Particular attention will be paid to potential compensation by the 5-HT1B receptor, including studies of feeding behavior and energy balance in "double-mutant" mice lacking both the 5-HT2C and 5-HT1B receptor subtypes. Studies of Aim 4 will identify brain regions and transmitter systems through which 5-HT2C receptors may regulate feeding. Hypotheses generated from the results of aim 4 will be tested in Aim 5 through the development of mice in which 5-HT2C receptor mutations are localized to restricted brain regions and cell types.

描述：（改编自研究者的摘要）脑5-羟色胺系统 与正常喂养行为的调节和 在饮食失调中观察到的进食失调。几行 证据表明5-羟色胺5-HT2C受体亚型有助于 大量抑制食物摄入的血清素能抑制。与 这，缺乏功能性setotonin 5-HT2C受体显示的小鼠显示降低 对通过5-羟色胺系统作用的食欲抑制药物的敏感性。 另外，这些动物表现出喂养行为的失调 慢性食物摄入量，晚期（“中年”）肥胖症和 增强了对2型糖尿病的敏感性。肥胖的几个特征 综合征让人联想到人类状况的共同形式。它是提出的 5-HT2C受体突变体提供了独特的遗传模型，其中肥胖症 喂养行为的主要缺陷而不是直接效果的结果 能源消耗突变。除了检验这一假设外， 5-HT2C受体调节喂养的神经机制是 探索。在AIM 1中，将对进食行为进行详细研究 检验5-HT2C受体突变体补偿其的假设 通过增加能量支出和随后的肥胖结果来暴饮暴食 从年龄依赖于维持这一补偿的失败。在AIM 3中， 5-羟色胺系统补偿5-HT2C受体的机制 将探索突变。特别关注潜力 5-HT1B受体的补偿，包括研究喂养行为和 缺少5-HT2C和5-HT1B的“双突变”小鼠的能量平衡 受体亚型。 AIM 4的研究将识别大脑区域和发射器 5-HT2C受体可以调节进食的系统。假设 AIM 4的结果产生的将在AIM 5中测试 5-HT2C受体突变所定位到的小鼠的发展 受限制的大脑区域和细胞类型。